Cellular mechanisms that mediate steatohepatitis, an increasingly prevalent condition in the Western world for which no therapies are available, are poorly understood. Using human genome wide association studies, we recently identified TTC39B (T39), which encodes a tetratricopeptide repeat-domain protein of unknown function, as a novel gene influencing HDL cholesterol levels. We have sought to understand the functions of T39 and its potential significance for human diseases using mouse models. These studies have revealed that T39 deficient mice are protected from development of fatty liver, steatohepatitis and atherosclerosis. T39 appears to be a scaffolding protein that regulates the post-transcriptional degradation of LXR, a transcription factor controlling cholesterol efflux genes and well as genes promoting triglyceride synthesis. In addition to beneficial lipoprotein changes and reduced atherosclerosis, T39 deficiency protects from hepatic steatosis and steatohepatitis when mice are challenged with high fat/high cholesterol diets, and the underlying mechanisms of these novel observations will be the main focus of this proposal. We will also explore the basic functions of T39 such as its ability to facilitate ubiquitination and degradation of LXR. Aim 1 will assess the mechanisms of reduced hepatic steatosis in T39-/- mice, Aim2 will determine tissue-specific effects of T39 in liver, spleen and hematopoietic cells; Aim 3 will explore the mechanisms of the post- transcriptional increase in LXR protein in T39-/- hepatocytes. These studies have the potential to uncover new treatments for steatohepatitis and atherosclerosis.